Hierarchical Microplates as Drug Depots with Controlled Geometry, Rigidity, and Therapeutic Efficacy

Abstract

A variety of microparticles have been proposed for the sustained and localized delivery of drugs with the objective of increasing therapeutic indexes by circumventing filtering organs and biological barriers. Yet, the geometrical, mechanical, and therapeutic properties of such microparticles cannot be simultaneously and independently tailored during the fabrication process to optimize their performance. In this work, a top-down approach is employed to realize micron-sized polymeric particles, called microplates (μPLs), for the sustained release of therapeutic agents. μPLs are square hydrogel particles, with an edge length of 20 μm and a height of 5 μm, made out of poly(lactic- co-glycolic acid) (PLGA). During the synthesis process, the μPL Young's modulus can be varied from 0.6 to 5 MPa by changing the PLGA amounts from 1 to 7.5 mg, without affecting the μPL geometry while matching the properties of the surrounding tissue. Within the porous μPL matrix, different classes of therapeutic payloads can be incorporated including molecular agents, such as anti-inflammatory dexamethasone (DEX), and nanoparticles containing imaging and therapeutic molecules themselves, thus originating a truly hierarchical platform. As a proof of principle, μPLs are loaded with free DEX and 200 nm spherical polymeric nanoparticles, carrying DEX molecules (DEX-SPNs). Electron and fluorescent confocal microscopy analyses document the uniform distribution and stability of molecular and nanoagents within the μPL matrix. This multiscale, hierarchical microparticle releases DEX for at least 10 days. The inclusion of DEX-SPNs serves to minimize the initial burst release and modulate the diffusion of DEX molecules out of the μPL matrix. The biopharmacological and therapeutic properties together with the fine tuning of geometry and mechanical stiffness make μPLs a unique polymeric depot for the potential treatment of cancer, cardiovascular, and chronic, inflammatory diseases.

Insulin Granule-Loaded MicroPlates for Modulating Blood Glucose Levels in Type-1 Diabetes

“…The thinner microparticles presented an overall faster release rate with 78.8 ± 0.1% of the insulin being released from the 5H INS-μPLs at 30 days, as opposed to the 55.6 ± 18.5% measured for the 10H INS-μPLs ( Figure 4 c). In line with previous studies by the authors, 35 − 39 it was here hypothesized that insulin could be released from the μPL upon dissolution of INS and the progressive diffusion of the molecular insulin out of the PLGA matrix. Based on this, we selected the 10H INS-μPL as the best configuration for the functional and in vivo studies as it provides an intermediate release profile: sufficiently faster than the 20H INS-μPL to possibly prevent hyperglycemic conditions within the first hours of the application; sufficiently slower than the 5H INS-μPL to guarantee a sustained insulin release for at least 30 days ( Figure 4 c).…”

“…INS-μPLs were obtained using a replica molding multi-step, top-down fabrication process. 35 , 36 Briefly, a direct laser writing process was adopted to realize silicon master templates with an array of 20 × 20 μm squared wells whose depth can range from a few microns to several tens of microns to modulate the thickness of the resulting microparticles. These master templates were replicated into polydimethylsiloxane (PDMS) templates which were then replicated into a sacrificial PVA templates ( Figure S1 ).…”

Quantitative micro-Raman analysis of micro-particles in drug delivery

“…1). Samples were obtained from multiple replica-molding steps, starting from a silicon master template, as described by Di Francesco et al 46 Briefly, the surface of a silicon wafer is patterned with an array of rectangular wells of the aforementioned dimensions, separated by a gap of 20 μm, extended over large areas, up to 3 × 3 cm (Fig. 1a).…”

Bottom‐Up versus Top‐Down Strategies for Morphology Control in Polymer‐Based Biomedical Materials

“…dexamethasone containing 200 nm spherical polymeric nanoparticles, and also free dexamethasone. [114] Both the molecular and nanoparticle cargos were found to be distributed evenly through the PLGA microparticles with confocal microscopy and electron microscopy imaging. The multiscale hierarchical nature of this drug delivery system proved to slow the burst release and control the diffusion of dexamethasone from the PLGA carrier.…”